Sp4 pathway in hippocampus modulates sensorimotor gating

海马 Sp4 通路调节感觉运动门控

基本信息

批准号：
7575828
负责人：
MARK A GEYER
金额：
$ 22.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7575828
关键词：
7p15 A Mouse Ablation Adult Affect Animal Model Animals Attention deficit hyperactivity disorder Autistic Disorder Behavior Behavioral Bipolar Disorder Brain Brain Diseases Breeding Cell Culture Techniques Cells Chromosomes Clinical Complex DRD1 gene Deformity Disease Dopamine Dopamine Antagonists Dopamine D1 Receptor Down-Regulation Drosophila genus Environment Family Functional disorder Future G Protein-Coupled Receptor Signaling G protein coupled receptor kinase Gene Expression Genes Genetic Glutamates Hippocampus (Brain)Homologous Gene Human Internal Ribosome Entry Site Knock-out Knockout Mice Maps Measures Mediating Memory Memory impairment Mental disorders Modeling Molecular Molecular Abnormality Molecular Probes Mus Mutant Strains Mice Neural Pathways Neurotrophin 3 Panic Disorder Pathway interactions Phenotype Play Predisposition Rattus Receptor Gene Research Personnel Rodent Role Schizophrenia Sensory Signal Pathway Stimulus System Tamoxifen Testing Untranslated Regions Virus Work base dentate gyrus desensitization desmoplakin endophenotype genetic manipulation granule cell information processing insight mutant neural circuit neuropsychiatry novel prepulse inhibition receptor research study response restoration transcription factor

项目摘要

DESCRIPTION (provided by applicant): Hippocampal abnormalities are important susceptibility factors for several human psychiatric disorders. Sensorimotor gating, assessed by prepulse inhibition of startle, is reduced in and provides a cross-species endophenotype for a group of psychiatric gating disorders, including schizophrenia, bipolar disorder, autism, and ADHD. In preliminary work, hypomorphic Sp4 mutant mice displayed vacuolization in the hippocampal dentate gyrus, reduced expression of the Grk4 gene in the hippocampus and cortex, robust deficits in sensorimotor gating and contextual memory, and decreased exploration of novel environments. The molecular, hippocampal, and behavioral abnormalities of the Sp4 mutant mice mimic several phenotypes for neuropsychiatric gating disorders. Specific Aim 1 will assess the cell autonomous roles of the Sp4 gene in the vacuolization of dentate gyrus, and the associated deficits in sensorimotor gating and contextual memory. A mouse line will be created with an inducible cre-ERT2 gene fused within the 3' UTR of the endogenous Desmoplakin (Dsp) gene by internal ribosome entry site without knocking-out Dsp expression. Tamoxifen will be used to activate the ere that in turn will reactivate or ablate the Sp4 expression in dentate granule cells. Hippocampal structural and functional abnormalities will be assessed in these rescue or conditional knockout mice. Specific Aim 2 will identify Sp4-mediated genetic pathways in the hippocampus that subserve novel object exploration. Studies will (a) further analyze the defective novelty exploration of the hypomorphic Sp4 mice in established paradigms; (b) examine whether the restoration or ablation of Sp4 expression in the dentate granule cells (Aim 1) can rescue or cause the defective novelty response. Specific Aim 3 will examine the role of the Grk4-mediated signaling pathway in the modulation of sensorimotor gating in Sp4 hypomorphic mice, using both pharmacological and genetic approaches. Cell culture experiments will examine Grk4-mediated desensitization of both dopamine D1 and mGluRI receptors in the Sp4 mutant hippocampal cells. Antagonists of dopamine D1 and mGluRI receptors will be administered to the hypomorphic Sp4 mutant mice to test for reversal of the prepulse inhibition deficit. To evaluate the disruption of Grk4-mediated GPCR signaling pathway in the modulation of sensorimotor gating and hippocampal vacuolization, double knockout mice combining the Sp4 deletion with either dopamine D1 or mGluRI receptor genes will be generated. These experiments will yield novel insights into genetic pathways within the hippocampus that underlie behavioral abnormalities relevant to several psychiatric disorders.

描述（由申请人提供）：海马异常是几种人类精神疾病的重要敏感性因素。通过预脉冲抑制惊吓来评估的感觉运动门控减少了，并为一组精神病学疾病（包括精神分裂症，双相情感障碍，自闭症和ADHD）提供了跨物种的内表型。在初步的工作中，肌张杆菌齿状回的脂肪型SP4突变小鼠在海马齿状回，降低了海马和皮质中GRK4基因的表达，感觉运动门控和上下文记忆中的稳健缺陷，并减少了新颖环境的探索。 SP4突变小鼠的分子，海马和行为异常模仿了神经精神病学疾病的几种表型。特定的目标1将评估SP4基因在齿状回液泡中的细胞自主作用，以及感觉运动门控和上下文记忆中相关的缺陷。将使用内源性脱氨基链霉素（DSP）基因的3'UTR中融合的诱导CRE-ERT2基因通过内部核糖体进入位点融合而产生小鼠线。他莫昔芬将被用来激活齿状颗粒细胞中的Sp4表达反过来激活。在这些救援或条件敲除小鼠中，将评估海马结构和功能异常。特定的目标2将在海马中识别SP4介导的遗传途径，这些途径可以予以研究。研究将（a）进一步分析已建立范式中型SP4小鼠的新颖性探索；（b）检查齿状颗粒细胞中Sp4表达的恢复或消融是否可以拯救或引起有缺陷的新颖性反应。特定的目标3将使用药理学和遗传方法检查SP4肌电运动小鼠中GRK4介导的信号传导途径在SP4肌电运动门控的调节中的作用。细胞培养实验将检查SP4突变体海马细胞中多巴胺D1和mgluri受体的GRK4介导的脱敏。多巴胺D1和MGLURI受体的拮抗剂将被施用到肌莫尔SP4突变小鼠上，以测试预硫化抑制不足的逆转。为了评估GRK4介导的GPCR信号通路的破坏在感觉运动门控和海马吸尘器中，将产生将SP4缺失与多巴胺D1或Mgluri受体基因相结合的双基因敲除小鼠。这些实验将产生对海马内遗传途径的新见解，这是行为异常与几种精神疾病相关的基础。